19
Oligosaccharidoses and Related Disorders
Generoso Andria, Giancarlo Parenti
19.1 Introduction
The oligosaccharidoses are a group of lysosomal storage disorders characterized by defects of glycoprotein degradation due to the deficiency of specific lysosomal enzymes (Fig. 19.1). All are inherited as autosomal recessive
traits.
The diagnosis is suggested by the clinical picture. Two general features
of lysosomal storage diseases need to be considered. First, although some
signs are quite specific or even pathognomonic, an overlap in the clinical
presentation often exists between the oligosaccharidoses and other lysosomal storage disorders, and the mucopolysaccharidoses (see Chap. 17).
Second, the same enzymatic defect can be responsible for different clinical
presentations, variable age of onset, severity and organ involvement. Section 19.4 summarizes the clinical features observed in oligosaccharidoses
and related disorders with an early (infantile) presentation, and symptoms
described in the late onset types. The same enzymes are responsible for
both the early and late onset variants.
Once a lysosomal storage disorder has been considered in a differential
diagnosis, a laboratory evaluation must be initiated in order to define biochemically the diagnosis. Two types of urinary screening tests are easily accessible to look for the abnormal excretion of either oligosaccharides or
mucopolysaccharides. If positive, this suggests either a disorder in the metabolism of oligosaccharides or of the mucopolysaccharides. The final diagnosis always requires specific enzymatic confirmation in the appropriate
biological material (generally leukocytes or cultured skin fibroblasts extracts, rarely plasma). When the screening tests are negative but suspicion
is still high, the resolution of the diagnosis may be provided by various assays of lysosomal enzymes, selected on the basis of a thorough clinical examination. A clinical approach, combined with simple laboratory tests, is
suggested in the diagnostic flow-charts (see Figs. 19.2, 19.3). Due to the extreme phenotypic variability of many of these disorders, all proposed diagnostic flow-charts cannot replace the critical evaluation of the astute clinician.
400
Oligosaccharidoses and Related Disorders
The features of lysosomal storage disorders do not meet the requirements for mass screening programs of patients. However, an approach
based on the detection of markers, such as lysosomal-associated membrane
proteins (LAMP-1 and LAMP-2), has been recently proposed for mass
screening of patients with lysosomal storage diseases. Carrier screening
programs have been proposed or implemented in populations where a certain disorder is particularly frequent. Examples are aspartylglucosaminuria
in Finland or Tay-Sachs disease and Gaucher disease, quite common among
Ashkenazi Jews (carrier frequency of 0.032 and 0.10, respectively).
Until a few years ago no efficacious treatment was available for lysosomal storage disorders and a biochemically defined diagnosis was requested
only for the genetic counseling, eventually leading to a prenatal diagnosis
in pregnancies at risk. Recently, exciting progresses have been made in the
treatment of lysosomal storage disorders, based on bone marrow transplantation or enzyme replacement, as in Gaucher disease and other lysosomal
storage disorders. In this respect, any patient with a suspicion of lysosomal
storage disease is a potential candidate for new therapeutic strategies and
deserves a precise diagnosis.
19.2 Nomenclature
No.
Disorder
Oligosaccharidoses
19.1.1
a-Mannosidosis type I
19.1.2
a-Mannosidosis type II
19.2.1
b-Mannosidosis infantile
19.2.2
b-Mannosidosis juvenile/adult
19.3
Fucosidosis
19.4.1
Sialidosis severe infantile
19.4.2
Sialidosis mild infantile (mucolipidosis I)
19.4.3
Sialidosis adult
19.5.1
Galactosialidosis (early infantile)
Enzyme/protein defect
Chromosome
localization
McKusick
number
a-Mannosidase
19cen-q12
248500
b-Mannosidase
4q22-q25
248510
a-Fucosidase
a-Neuraminidase
1p34
6p21.3
230000
256550
“Protective protein”/cathepsin 20q13.1
A deficiency
(Secondary b-galactosidase
and a-neuraminidase deficiencies)
19.5.2
Galactosialidosis (late infantile)
19.5.3
19.6
19.7.1
19.7.2
Galactosialidosis (juvenile/adult)
Aspartylglucosaminuria
Aspartylglucosaminidase
a-NAGA deficiency type I (Schindler disease) a-N-acetylgalactosaminidase
a-NAGA deficiency type II (Kanzaki disease)
4q32-q33
22q11
256540
208400
104170
Nomenclature
No.
Disorder
Related disorders
19.8.1
GM1 gangliosidosis (early infantile)
19.8.2
GM1 gangliosidosis (late infantile)
19.8.3
GM1 gangliosidosis (adult)
19.9.1
GM2 gangliosidosis variant B, infantile
(Tay-Sachs disease)
19.9.2
Variant B, late onset
19.9.3
Variant 0, infantile (Sandhoff disease)
19.9.4
Variant 0, juvenile/adult
19.9.5
Variant AB
19.10
Mucolipidosis II (I-cell disease)
19.11
Mucolipidosis III
19.12
Mucolipidosis IV
19.13.1
19.13.2
19.13.3
19.13.4
19.14.1
19.14.2
19.14.3
19.15.1
Gaucher disease
Type 1 (“adult”, chronic nonneuronopathic)
Type 2 (acute neuronopathic)
Type 3 (subacute neuronopathic)
Gaucher disease (SAPC deficiency)
Niemann-Pick disease type A
Niemann-Pick disease type B
Niemann-Pick disease type B (adult)
Niemann-Pick disease type C (acute)
19.15.2
19.15.3
19.16.1
19.16.2
19.17
Niemann-Pick disease type C (classic)
Niemann-Pick disease type C (adult)
Krabbe disease infantile
Krabbe disease late onset
Multiple sulfatase deficiency
Enzyme/protein defect
Chromosome
localization
McKusick
number
b-Galactosidase
3p21.33
230500
b-Hexosaminidase A
(b-subunit)
15q23-q24
272800
b-Hexosaminidase A and B
(a-subunit)
b-Hexosaminidase activator
N-acetylglucosamine 1-phosphotransferase (secondary
multiple lysosomal enzyme
deficiencies)
N-acetylglucosamine 1-phosphotransferase (secondary
multiple lysosomal enzyme
deficiencies)
Mucolipidin (receptor-stimulated cation channel)
b-Glucocerebrosidase
5q13
268800
5q31.3-q33.1
4q21-q23
272750
252500
4q21-q23
252500
19p13.3-p13.2
252650
1q21
230800
SAPC
Sphingomyelinase
10q22.1
11p15.4-p15.1
176801
257200
Abnormal intracellular
cholesterol transport
18q11-q12
257220
b-Galactocerebrosidase
14q31
245200
Posttranslational modification of a cysteine in at least
12 sulfatases
272200
401
402
Oligosaccharidoses and Related Disorders
19.3 Metabolic Pathway
Fig. 19.1. Degradation of
complex oligosaccharides
The degradation of a hypothetical complex oligosaccharide by lysosomal
enzymes known to be deficient in human diseases. This is only an example
of a complex molecule which can accumulate in oligosaccharidoses. The
numbers in bold indicate the diseases (listed in Sect. 19.2) in which the defect in the cleavage of a specific glycosidic bond (in italics) is present. A
variety of oligosaccharides can accumulate in body fluids and tissues as a
consequence of the enzymatic defects; however, structural studies of the
storage compound are not relevant to the diagnosis. The demonstration of
an abnormal oligosacchariduria by thin-layer chromatography (TLC) is the
only established screening test for this group of diseases. The final diagnosis relies upon the demonstration of the specific enzyme defect. Asn =
asparagine; Fuc = fucose; GlcNAc = N-acetylglucosamine; Man = mannose;
Gal = galactose; SA = sialic acid (modified according to ref. [1]).
Signs and Symptoms
403
19.4 Signs and Symptoms
Table 19.1. Oligosaccharidoses with early infantile presentation
System
Symptoms/markers
Disorders
19.1.1
19.2.1
19.3
19.4.1
19.4.2
19.5.1
19.5.2
19.6
Clinical
Age (yr) at onset
course
Age (yr) at death
Frequency
<1
<10
100
cases
1–2
a
10
cases
<1–2
<10–a
100
cases
<0.5
<1–7
<20
cases
<1–3
10–20
<50
cases
<0.3
<2
20
cases
1–3
a
<20
cases
Facies
++
+
+
+
++
±
++
±
++
±
++
+
1–5
<1
a
100
very
cases; rare
Finnish:
1:17000
+
±
±
+
+
+
++
+
±
±
++
++
+
+
++
++
++
++
+
+
+
+
±
+
+
+
±
+
+
±
±
+
++
+
±
±
±
±
+
±
++
+
Skeleton
Eye
Ear
CNS
Cardiac
Hurler-like phenotype
Macrocephaly
Microcephaly
Short stature/growth
disturbance
Disostosis multiplex
Vertebral changes
Osteolysis/osteonecrosis
Corneal opacities
Lens opacities
Cherry-red spot
Optic atrophy
Hearing loss
Mental retardation
Progressive neurological
course/dementia
Seizures
Startle reaction to sound
Myoclonus
Ataxia
Pyramidal signs spasticity
Hypotonia
Ophthalmoplegia/strabismus
Hypertrophy/valvular thickening
Kidney involvement/edema
Hepatomegaly
Splenomegaly
Hernias
Angiokeratoma
Renal
Liver
Spleen
GI
Dermatologic
Special
Vacuolar lymphocytes/foamy
laboratory bone marrow
histiocytes
Reduced nerve conduction
velocity
Increased acid phosphatase
a, Adulthood; blank, not reported.
++
+
+
++
+
±
+
+
±
++
+
++
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
±
±
±
+
+
+
+
+
+
+
±
±
±
+
+
+
+
++
++
++
+
+
+
+
++
+
+
+
+
+
+
+
++
++
++
++
+
+
19.7.1
+
+
++
++
+
±
+
+
+
+
+
404
Oligosaccharidoses and Related Disorders
Table 19.2. Other lysosomal storage disorders with early (infantile) presentation
System
Symptoms/markers
Disorders
19.8.1
19.8.2
19.9.1
Clinical course Age (yr) at onset
Age (yr) at death
Frequency
<0.5
<2
rare
0.5–2
3–10
<0.5
<0.5
2–4
2–4
1:300000 1:300000
Non-Jewish
1:4000
Jewish
Facies
+
±
Skeleton
Eye
Ear
CNS
Cardiac
Renal
Liver
Spleen
GI
Dermatologic
Special
laboratory
Hurler-like phenotype
Macrocephaly
Microcephaly
Short stature/growth
disturbance
Disostosis multiplex
Vertebral changes
Osteolysis/osteonecrosis
Chondrodysplasia punctata
Corneal opacities
Lens opacities
Cherry-red spot
Optic atrophy
Retinal degeneration
Hearing loss
Mental retardation
Progressive neurological
course/dementia
Seizures
Startle reaction to sound
Myoclonus
Ataxia
Pyramidal signs/spasticity
Hypotonia
Ophthalmoplegia/strabismus
Hypertrophy/valvular thickening
Kidney involvement/edema
Hepatomegaly
Splenomegaly
Hernias
Angiokeratoma
Ichthyosis
Vacuolar lymphocytes/foamy
bone marrow histiocytes
Reduced nerve conduction
velocity
Increased acid phosphatase
a, Adulthood; blank, not reported.
19.9.3
19.9.5
19.10
<0.5
2–4
very rare
0–1
5–8
rare
++
+
+
+
+
+
++
±
+
++
+
+
+
+
+
+
++
++
++
+
++
++
++
++
++
++
+
+
+
+
++
++
++
++
++
++
++
+
+
+
+
+
+
+
++
±
+
+
+
+
±
±
++
±
+
±
+
Signs and Symptoms
405
19.11
19.12
19.13.2
19.13.3
19.14.1
19.14.2
19.15.1
19.15.2
19.16.1
19.17
2–4
a
rare
0–1
<1
<2
1:500000
<1–20
0–1
<5
rare
0.3
0.2
<8
1:150000
0–20
<1–a
<0.5
1–2
1:100000
<1
3–10
50 cases
rare
1:100000
±
+
+
+
+
+
+
+
+
+
+
±
++
±
+
++
+
±
+
+
+
±
±
±
+
+
++
++
++
++
+
++
+
±
++
+
++
++
+
+
+
+
++
++
+
+
+
+
++
+
++
++
±
±
++
++
++
++
++
++
++
++
+
+
+
+
+
++
++
++
++
++
++
+
+
++
+
+
+
+
+
++
++
406
Table 19.3. Oligosaccharidoses and related disorders with late (juvenile/adult) presentation
Symptoms/markers
Disorders
19.1.2
19.2.2
19.4.3
19.5.3
19.7.2
19.8.3
19.9.2
19.9.4
19.13.1
Clinical
Age (yr) at onset
course
Age (yr) at death
Frequency
1–4
a
100
cases
10–20
a
10
cases
10–20
a
<20
cases
10–20
a
50
cases
>20
<10
>20
rare
2–15
10–20
rare
3–30
<1–a
>20
a
1:60000
rare
non-Jewish
1:600 Jewish
Facies
±
++
+
Skeleton
Eye
Ear
CNS
Hurler-like phenotype
Macrocephaly
Microcephaly
Short stature/growth
disturbance
Disostosis multiplex
Vertebral changes
Osteolysis/osteonecrosis
Chondrodysplasia
punctata
Corneal opacities
Lens opacities
Cherry-red spot
Optic atrophy
Retinal degeneration
Hearing loss
Mental retardation
Progressive neurological course/dementia
Seizures
Startle reaction to
sound
Myoclonus
Ataxia
Pyramidal signs/
spasticity
Hypotonia
Ophthalmoplegia/
strabismus
very
rare
rare
19.14.3
19.15.3
19.16.2
>20
3–10
1:150000 rare
+
+
+
+
±
+
++
+
++
+
+
++
++
+
+
+
±
±
±
++
+
±
±
++
+
±
+
+
+
+
+
+
++
+
+
++
+
±
+
+
±
+
+
+
+
±
+
+
±
+
+
+
+
+
±
+
+
+
+
+
+
Oligosaccharidoses and Related Disorders
System
Table 19.3 (continued)
System
Symptoms/markers
Disorders
19.1.2
Cardiac
Renal
Liver
Spleen
GI
Dermatologic
Hypertrophy/valvular
thickening
Kidney involvement/
edema
Hepatomegaly
+
Splenomegaly
+
Hernias
Angiokeratoma
Ichthyosis
Special
Vacuolar lympholaboratory cytes/foamy bone
marrow histiocytes
Reduced nerve conduction velocity
Increased acid phosphatase
+
19.2.2
19.4.3
19.5.3
19.7.2
19.8.3
19.9.2
19.9.4
19.13.1
19.14.3
19.15.3
++
++
+
+
±
±
++
++
±
19.16.2
++
+
+
±
+
++
+
±
±
++
a, Adulthood; blank, not reported.
Signs and Symptoms
407
408
Oligosaccharidoses and Related Disorders
19.5 Laboratory Diagnosis
The diagnosis of oligosaccharidoses and related disorders relies upon the
assay of the deficient enzymatic activities. For all of them DNA analysis is
also available and, if required, can be used. For mucolipidosis IV an enzymatic assay is not available, but molecular analysis is feasible and can be
used for prenatal diagnosis.
Disorder Enzyme defect c
Oligosaccharides (U) d
Material
Postnatal diagnosis Prenatal diagnosis
19.1
19.2
19.3
19.4
19.5
19.6
19.7
19.8
19.9
19.10
19.11
19.13
19.14
19.15
19.16
19.17
a
a-Mannosidase
b-Mannosidase
a-Fucosidase
a-Neuraminidase
a-Neuraminidase and b-galactosidase
(secondary deficiencies)
Aspartylglucosaminidase
a-N-Acetylgalactosaminidase
b-Galactosidase
b-Hexosaminidase A and B
N-Acetylglucosamine 1-phosphotransferase
Multiple lysosomal enzyme activities
(secondary deficiencies)
N-Acetylglucosamine 1-phosphotransferase
Multiple lysosomal enzyme activities
(secondary deficiencies)
b-Glucocerebrosidase
Sphingomyelinase
Abnormal cholesterol esterification
b-Galactocerebrosidase
Multiple sulfatase activities
WBC, FB
WBC, FB
WBC, FB
FB
FB b
CV, AFC
CV, AFC
CV, AFC
CCV, AFC
CCV, AFC
:
:
:
:
:
WBC, FB
WBC, FB
WBC, FB
P, WBC, FB
FB
FBb
CV, AFC
CV, AFC
CV, AFC
CV, AFC
CV
CCV, AFC
:
:
:
:a
:
FB
FBb
CV
CCV, AFC
:
WBC, FB
WBC, FB
FB
WBC, FB
P, WBC, FB
CV, AFC
CCV, AFC
CCV, AFC
CV, AFC
CV, AFC
Only in GM2 gangliosidosis, variant 0 (Sandhoff disease).
Diagnosis is also based on high levels of some extracellular enzyme activities (b-hexosaminidase, arylsulfatase A,
a-mannosidase, etc.) in plasma or amniotic fluid supernatant.
c
Diagnostic tests. The diagnosis of this group of lysosomal storage disorders relies upon the demonstration of a profound deficiency of a specific enzymatic activity, assayed in the appropriate material (as indicated in this table). Since
assay conditions are very variable in relation to type of substrate, source of enzyme, etc. no reference values are given
here. The physician should refer to the normal range of enzymatic activity under established assay conditions, as provided by the diagnostic laboratory. The interpretation of the results is generally clear-cut, since enzymatic activities in
controls are much higher than in patients, but can overlap with the heterozygote range. An apparently normal enzymatic activity can be found in vitro for some variants of lysosomal disorders due to in vivo deficiency of an activator
of the enzyme: this is seen, for example, in some cases of Sandhoff disease and Gaucher disease and requires a more
complex and careful laboratory workup. Enzymatic pseudodeficiencies have also been reported for some lysosomal
storage diseases, such as metachromatic leukodystrophy and GM2 gangliosidosis.
d
Screening tests: Thin-layer chromatography of urinary oligosaccharides is the most useful, simple and reliable screening test for this group of diseases (see Chap. D for the interpretation).
b
Diagnostic Flow Charts
409
19.6 Diagnostic Flow Charts
Clues to the
diagnosis
Clinical
presentations
Mental
retardation a
Mental
retardation
Visceromegaly
Vacuolated
lymphocytes
foamy histiocytes
Mental
retardation
Hurler-like
phenotype b
Mental
retardation
Visceromegaly
Visceromegaly
Visceromegaly
Visceromegaly
Vacuolated
lymphocytes
foamy histiocytes
Vacuolated
lymphocytes
foamy histiocytes
Vacuolated
lymphocytes
foamy histiocytes
Vacuolated
lymphocytes
foamy histiocytes
Hurler-like
phenotype
Hurler-like
phenotype
Macular cherry-red spot d
Y
Suggested
Diagnoses c
• GM2 gangl. 0
(100 %)
• GM2 gangl. B
(100 %)
N
Y
N
Y
N
Y
• Sialidosis
• Niemann
• α-NAGA • Niemann-Pick d.
Pick d. B • Gaucher sev. inf. (25 %)
def. type I A (50 %)
(rare)
d. type 1 • Sialidosis
• Krabbe d.
mild. inf. (100 %)
•
Gaucher
d.
• Metachromatic
• Galactosialidosis
types
2,
3
leukodysrophy
early inf. (30 %)
• Niemann-Pick d.
• GM1 gangl.
C acute, classic
early inf. (50 %)
N
• α-Mannosidosis •
• Fucosidosis
• Aspartylglucosaminuria e
• GM1 gangl.
late inf. e
• Mucolipidosis II, III
• MPS IH, II, III, VII
• Multiple sulf. def.
• Infantile sialic acid
storage d.
Y
N
Galacto- • MPS IS,
sialidosis VI
Late inf.
(50 %)
Fig. 19.2. Clinical approach to the diagnosis of oligosaccharidoses and related lysosomal disorders with early (infantile) onset. a Associated with CNS involvement of various types. b Facial dysmorphism and/or skeletal (vertebral) involvement suggestive of dysostosis multiplex. c Bold: conditions associated with abnormal oligosacchariduria; italics:
conditions associated with abnormal mucopolysacchariduria. d The percentage of patients showing macular cherry-red
spot (when present) is indicated in parentheses. e Absence of visceromegaly
410
Oligosaccharidoses and Related Disorders
Coarse Hurler-like face
Abnormal mucopolysacchariduria
Y
N
Mucopolysaccharidoses
Abnormal oligosacchariduria
Y
Oligosaccharidoses and
related disorders
N
Other non-metabolic
disorders *
Fig. 19.3. Diagnostic flow-chart for patients with coarse
Hurler-like face. *Coffin-Lowry syndrome (MIM 303300);
Coffin-Siris syndrome (MIM 135900); frontometaphyseal
dysplasia (MIM 305620); Sotos syndrome (MIM 117550);
Williams syndrome (MIM 194050); multiple neuroma
syndrome (MIM 171400); pachydermoperiostosis (MIM
167100); acromegaloid facial appearance syndrome (MIM
102150); Costello syndrome (MIM 218040); Patterson David
syndrome (MIM 169170); Schinzel-Giedeon syndrome
(MIM 269150); Fountain syndrome (MIM 229120); PallisterKillian syndrome (MIM 601803); Simpson-Golabi-Behmel
syndrome (MIM 312870); congenital hypothyroidism. Sialic
acid storage disease, a lysosomal transport defect (Chap. 20)
should also be considered in the differential diagnosis
19.7 Summary
Oligosaccharidoses are inherited diseases showing relevant clinical overlap
with other related lysosomal disorders. Analysis of undegraded and accumulated metabolites is used as a screening test only, for oligosaccharidoses
as well as for mucopolysaccharidoses. A profound deficiency of a specific
enzyme has to be demonstrated for a biochemically defined diagnosis of
these diseases. Progresses in molecular genetics have already modified the
approach to prenatal, postnatal and heterozygote diagnosis. In the next
future they are expected to lead to new forms of treatment, including gene
therapy.
References
1. Scriver C.R., Beaudet A., Valle D., Sly W.S. (eds.), The metabolic and molecular
bases of inherited disease. McGraw-Hill, New York, U.S.A., 2001, 8th edition. Chap.
138, 139, 140, 141, 144, 145, 146, 147, 149, 151, 152, 153
2. Durand P., O’Brien J.S., Genetic errors of glycoprotein metabolism. Edi-Ermes,
Milan, Italy, 1982.
3. Warner T.G., O’Brien J.S., Genetic defects in glycoprotein metabolism. Ann. Rev.
Genet., 17: 395–441, 1983